Age-related macular degeneration (AMD) is a leading cause of blindness in the U.S., affecting 8 million Americans over fifty years of age. Its cause is rooted in the highly oxidizing environment of the retina, which is simultaneously exposed to UV light and high oxygen tensions. Over a lifetime, oxidant events in the retina lead to accumulation of drusen, a complex aggregation of oxidized lipids and proteins, Advanced Glycation End-products (AGEs), activated complement and even Alzheimer's 2 peptide (A2). With time, drusen accumulation and the resulting inflammatory response produces apoptosis of retinal pigment epithelial (RPE) cells and exuberant growth of brittle choroidal vessels which can rupture, with abrupt loss of vision. GlycoMira has synthesized several partially lipophilic, sulfated derivatives of hyaluronic acid that show anti-inflammatory activities at nanogram/ml concentrations, including inhibition of complement activation, P-selectin and human leukocyte elastase (HLE). These sulfated and alkylated HA derivatives also potently antagonize the interaction of the Receptor for Advanced Glycation End-products (RAGE) with its many ligands, including carboxy-methyl lysine albumin (CML-BSA), S100 calgranulins, and high mobility box group protein-1 (HMGB-1). We hypothesize that these proprietary agents can be used as a novel therapy for AMD by inhibiting the myriad pro-inflammatory and angiogenic events in the AMD retina. In Aim 1, analogs will be synthesized and chemically characterized to explore structure-activity space by varying molecular size, sulfation and alkylation. In Aim 2, the inhibition of complement, RAGE activation, P-selectin and HLE will be tested in vitro. In Aim 3, we will evaluate the feasibility of using these compounds to antagonize AGE/RAGE-mediated apoptosis and expression of vascular endothelial growth factor (VEGF) in cultured human retinal epithelial cells. Using the most active compound from in vitro experiments, in Aim 4 we will the determine feasilibity of blocking VEGF-mediated choroidal neovascularization in mice using a laser photocoagulation model. Following this feasibility study, GlycoMira would pursue a Phase II project to leverage the development of an intra-vitreal formulation of our lead drug, demonstrate its efficacy by prevention of choroidal neovascularization in other models of retinal diseases, and complete the manufacturing and toxicology studies required for an investigational new drug application (IND). PUBLIC HEALTH RELEVANCE: Age-related macular degeneration (AMD) is the leading cause of blindness in the U.S., affecting 8 million Americans over fifty years of age. Over a life-time, oxidant events in the retina of susceptible individuals lead to accumulation of drusen, an amalgamation of oxidized lipids and proteins, Advanced Glycation EndproductS (AGEs), activated complement and even Alzheimer's 2 peptide, resulting in an inflammatory response that produces apoptosis of retinal pigment epithelial cells and exuberant new growth of brittle choroidal vessels which can rupture, with abrupt loss of vision. The current therapy for AMD, intravitreal injection of antibodies against vascular endothelial growth factor (VEGF), is expensive and imperfect. We propose to develop sulfated, partially lipophilic hylauronic acid derivatives as an anti-complement, anti-RAGE, anti-inflammatory and anti-angiogenic therapy for this devastating cause of blindness in older Americans.